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PSC-833, a frontier in modulation of P-glycoprotein mediated multidrug resistance
1Preclinical Research, Novartis Pharmaceutical Corporation, East Hanover, USA.
Abstract:
The expression of drug efflux mechanisms by cancer cells during chemotherapy leads to multidrug resistance (MDR) and constitutes a major obstacle in the effective treatment of cancer. The most widely characterized drug effluxes pump is P-glycoprotein (P-gp) and efforts are being directed towards identifying agents that reverse P-gp mediated drug resistance. PSC-833 is a non-immunosuppressive cyclosporin derivative that potently and specifically inhibits P-gp. The current review focuses on the elucidation of the mechanism of action of PSC-833 as a potential MDR reversing agent, using syngeneic multidrug resistant sublines of MDA435 human breast adenocarcinoma cell line that express increasing levels of P-gp. In vitro experiments indicate that PSC-833 interacts directly with P-gp with high affinity and probably interferes with the ATPase activity of P-gp. Studies in multidrug resistant tumor models confirm P-gp as the in vivo target of PSC-833 and demonstrate the ability of PSC-833 to reverse MDR leukemias and solid tumors in mice. Presently, PSC-833 is being evaluated in the clinic.
Insights
PSC-833, a novel agent, effectively reverses multidrug resistance (MDR) in cancer by inhibiting P-glycoprotein (P-gp). This drug shows promise in preclinical models and is currently in clinical trials for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Multidrug resistance (MDR) in cancer, mediated by drug efflux pumps like P-glycoprotein (P-gp), significantly hinders chemotherapy efficacy.
- Developing agents to reverse P-gp-mediated drug resistance is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To elucidate the mechanism of action of PSC-833, a P-gp inhibitor, as a potential MDR reversing agent.
- To evaluate PSC-833's efficacy in preclinical cancer models expressing varying levels of P-gp.
Main Methods:
- Utilized syngeneic multidrug resistant sublines of MDA435 human breast adenocarcinoma cells with increasing P-gp expression.
- Conducted in vitro experiments to assess PSC-833's interaction with P-gp and its ATPase activity.
- Evaluated PSC-833 in vivo in multidrug resistant mouse tumor models (leukemias and solid tumors).
Main Results:
- In vitro studies demonstrated PSC-833's high-affinity interaction with P-gp, likely interfering with its ATPase activity.
- In vivo studies confirmed P-gp as the target and showed PSC-833's ability to reverse MDR in various mouse tumor models.
- PSC-833 is a potent and specific inhibitor of P-gp without immunosuppressive effects.
Conclusions:
- PSC-833 effectively reverses P-glycoprotein-mediated multidrug resistance in cancer.
- Its mechanism involves direct interaction with P-gp, potentially inhibiting ATPase activity.
- PSC-833 shows significant therapeutic potential and is undergoing clinical evaluation.